The innate immune system senses the presence of microbes or damage via germline-encoded receptors, which detect pathogen associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Nucleic acids constitute a major molecular pattern that is recognized during infection by viruses or intracellular bacteria and that results in the stimulation of type I interferons (IFN-I) and other cytokines. However, chronic or inappropriate activation of nucleic acid-sensing pathways are also implicated in inflammatory and autoimmune diseases.
Evidence for the involvement of type I IFNs (IFN-I) in the pathogenesis of systemic autoimmune disorders such as systemic lupus erythematosus (SLE) (Elkon, K. B. and A. Wiedeman, Type I IFN system in the development and manifestations of SLE. Curr Opin Rheumatol, 2012. 24(5): p. 499-505) as well as in rare monogenic disorders including Aicardi-Goutierre's Syndrome (AGS) and spondyloenchondrodysplasia (SPENCD), is demonstrated by the increased expression of IFN-I stimulated genes (ISGs) in peripheral blood cells. SLE is a heterogeneous and flaring disease which can cause diseases of the skin, heart, lung, kidney, joints, nervous system etc., which make it very difficult to treat. AGS is a rare inherited ‘orphan’ disease that affects children. It is characterized predominantly by abnormalities in the skin and brain resulting in severe brain defects and even death in some of these children (˜35% of patients die by age 15). This disease is also associated with the expression of IFN-I and some of these patients develop features similar to SLE. In a reciprocal fashion, 1-2% of SLE patients have mutations in TREX1. The association of TREX1 mutations with SLE remains the strongest single association of a gene identified so far (highest odds ratio). There is currently no effective treatment for the severe, debilitating disorder of AGS.
How, where and when IFN-I is initially stimulated, and which of the approximately 20 IFN-I subtypes are expressed in each disease, has been difficult to determine. In vitro studies (Santer, D. M., et al., Potent induction of IFN-alpha and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. J Immunol, 2009. 182(2): p. 1192-201), have revealed that IFN-alpha (IFNa) is induced by SLE immune complexes (IC) containing (ribo)nucleoprotein antigens (Lovgren, T., et al., Induction of interferon-alpha by immune complexes or liposomes containing systemic lupus erythematosus autoantigen-and Sjogren's syndrome autoantigen-associated RNA. Arthritis Rheum, 2006. 54(6): p. 1917-27). However, the in vitro studies do not address how IFN-I may be induced prior to the formation of IC. Cytosolic DNA induces type I interferons and other cytokines which are important for antimicrobial defense but can also trigger autoimmunity. Experiments demonstrating that the serum from a significant proportion of SLE family members without autoantibodies induce ISGs in responder cells (Niewold, T. B., et al., High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus. Genes Immun, 2007. 8(6): p. 492-502) as well as incomplete neutralization of ISGs in clinical trials using biologics targeting IFN-α, suggest that other IFN-I may well be involved in SLE (Petri, M., et al., Sifalimumab, a human anti-interfron-alpha monoclonal antibody in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study. Arthritis Rheum, 2013. 65(4): p. 1011-21). Moreover, in a mouse model of AGS caused by deficient expression of the 3-5′ DNA exonuclease, TREX1, accumulation of intracellular DNA is responsible for cell intrinsic production of IFNb.
While many DNA sensors have been described, the recent discovery of cyclic GAMP synthase, (cGAS) (Wu. J., et al., Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science, 2013. 339(6121): p. 826-30) (Sun, L., et al., Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science, 2013. 339(6121): p. 786-91), is of particular interest as it has been shown to play a pivotal role in virus-induced as well as DNA damage-induced IFN-I production. Following binding of double stranded (ds)-DNA to a positively charged pocket of cGAS, the enzyme undergoes a conformational change revealing a catalytic cleft which results in the synthesis of the cyclic dinucleotide, cyclic GMP-AMP (cGAMP) (Diner, E. J., et al., The Innate Immune DNA Sensor cGAS Produces a Noncanonical Cyclic Dinucleotide that Activates Human SLING. Cell Rep, 2013. 3(5): p. 1355-61). cGAMP binds to the adapter protein, STING, which triggers activation of TBK, phosphorylation of IRF3 with resulting transcription of IFN-b (Sun, 2013) (Wu, 2013). In cells that are deficient in TREX1, it has recently been shown that DNA triggers IFN-b selectively through the cGAS pathway (Gao, D., et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc Natl Acad Sci USA 112, E5699-5705 (2015), 26371324); Gray, E. E., Treuting, P. M., Woodward, J. J., and Stetson. D. B. 2015. Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi-Goutieres Syndrome. J Immunol 195:1939-1943).
There remains a need in the art for treatment of severe debilitating diseases associated with IFN-I due to cGAS activation. Understanding the mechanism how cGAS/cGAMP contribute to IFN-I stimulation in SLE patients allows for directed therapeutic approaches which we are pursuing in SLE and possibly other autoimmune diseases associated with cytosolic DNA as a Danger Associated Molecular Pattern (DAMP).